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Mol. Cell. Biol. 20 (4): 1448-1459

Copyright © 2000 by the American Society for Microbiology. All rights reserved.

Molecular and Cellular Biology, February 2000, p. 1448-1459, Vol. 20, No. 4
Copyright © 2000, American Society for Microbiology. All rights reserved.

A Novel Positive Feedback Loop Mediated by the Docking Protein Gab1 and Phosphatidylinositol 3-Kinase in Epidermal Growth Factor Receptor Signaling

Gerard A. Rodrigues,dagger Marco Falasca,Dagger Zhongtao Zhang, Siew Hwa Ong,§ and Joseph Schlessinger*

Department of Pharmacology and Skirball Institute, New York University Medical Center, New York, New York 10016

Received 9 June 1999/Returned for modification 17 August 1999/Accepted 12 November 1999

The Gab1 protein is tyrosine phosphorylated in response to various growth factors and serves as a docking protein that recruits a number of downstream signaling proteins, including phosphatidylinositol 3-kinase (PI-3 kinase). To determine the role of Gab1 in signaling via the epidermal growth factor (EGF) receptor (EGFR) we tested the ability of Gab1 to associate with and modulate signaling by this receptor. We show that Gab1 associates with the EGFR in vivo and in vitro via pTyr sites 1068 and 1086 in the carboxy-terminal tail of the receptor and that overexpression of Gab1 potentiates EGF-induced activation of the mitogen-activated protein kinase and Jun kinase signaling pathways. A mutant of Gab1 unable to bind the p85 subunit of PI-3 kinase is defective in potentiating EGFR signaling, confirming a role for PI-3 kinase as a downstream effector of Gab1. Inhibition of PI-3 kinase by a dominant-interfering mutant of p85 or by Wortmannin treatment similarly impairs Gab1-induced enhancement of signaling via the EGFR. The PH domain of Gab1 was shown to bind specifically to phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3], a product of PI-3 kinase, and is required for activation of Gab1-mediated enhancement of EGFR signaling. Moreover, the PH domain mediates Gab1 translocation to the plasma membrane in response to EGF and is required for efficient tyrosine phosphorylation of Gab1 upon EGF stimulation. In addition, overexpression of Gab1 PH domain blocks Gab1 potentiation of EGFR signaling. Finally, expression of the gene for the lipid phosphatase PTEN, which dephosphorylates PtdIns(3,4,5)P3, inhibits EGF signaling and translocation of Gab1 to the plasma membrane. These results reveal a novel positive feedback loop, modulated by PTEN, in which PI-3 kinase functions as both an upstream regulator and a downstream effector of Gab1 in signaling via the EGFR.

* Corresponding author. Mailing address: Department of Pharmacology, MSB424, New York University Medical Center, 550 First Ave., New York, NY 10016. Phone: (212) 263-7111. Fax: (212) 263-7133.

dagger Present address: Allergan Inc., Irvine, CA 92623.

Dagger Present address: Department of Cell Biology and Oncology, Instituto di Ricerche Farmacologiche `Mario Negri' Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro (CH), Italy.

§ Present address: Signal Transduction Laboratory, Institute of Molecular and Cell Biology, Singapore 119076, Singapore.

Molecular and Cellular Biology, February 2000, p. 1448-1459, Vol. 20, No. 4
Copyright © 2000, American Society for Microbiology. All rights reserved.

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Mol. Cell. Biol. 22, 3744-3756
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Distinct Recruitment and Function of Gab1 and Gab2 in Met Receptor-mediated Epithelial Morphogenesis.
L. S. Lock, C. R. Maroun, M. A. Naujokas, and M. Park (2002)
Mol. Biol. Cell 13, 2132-2146
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The Adapter Molecule Gab2 Regulates Fc{epsilon}RI-Mediated Signal Transduction in Mast Cells.
Z.-H. Xie, I. Ambudkar, and R. P. Siraganian (2002)
J. Immunol. 168, 4682-4691
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Regulation of the Mitogen-activated Protein Kinase Signaling Pathway by SHP2.
J. M. Cunnick, S. Meng, Y. Ren, C. Desponts, H.-G. Wang, J. Y. Djeu, and J. Wu (2002)
J. Biol. Chem. 277, 9498-9504
   Abstract »    Full Text »    PDF »
PKB-mediated negative feedback tightly regulates mitogenic signalling via Gab2.
D. K. Lynch and R. J. Daly (2002)
EMBO J. 21, 72-82
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Regulation of c-fos Induction in Lens Epithelial Cells by 12(S)HETE-Dependent Activation of PKC.
R. K. Seth, M. S. R. Haque, and P. S. Zelenka (2001)
Invest. Ophthalmol. Vis. Sci. 42, 3239-3246
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Analysis of Corkscrew Signaling in the Drosophila Epidermal Growth Factor Receptor Pathway During Myogenesis.
M. R. J. Hamlet and L. A. Perkins (2001)
Genetics 159, 1073-1087
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Expression of Gab1 Lacking the Pleckstrin Homology Domain Is Associated with Neoplastic Progression.
H. Kameda, J. I. Risinger, B.-B. Han, S. J. Baek, J. C. Barrett, T. Abe, T. Takeuchi, W. C. Glasgow, and T. E. Eling (2001)
Mol. Cell. Biol. 21, 6895-6905
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Recruitment of the Class II Phosphoinositide 3-Kinase C2{beta} to the Epidermal Growth Factor Receptor: Role of Grb2.
M. Wheeler and J. Domin (2001)
Mol. Cell. Biol. 21, 6660-6667
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The Tyrosine Kinase Inhibitor ZD1839 (""Iressa"") Inhibits HER2-driven Signaling and Suppresses the Growth of HER2-overexpressing Tumor Cells.
M. M. Moasser, A. Basso, S. D. Averbuch, and N. Rosen (2001)
Cancer Res. 61, 7184-7188
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High resolution mapping of mast cell membranes reveals primary and secondary domains of Fc{epsilon}RI and LAT.
B. S. Wilson, J. R. Pfeiffer, Z. Surviladze, E. A. Gaudet, and J. M. Oliver (2001)
J. Cell Biol. 154, 645-658
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Regulation of ANP clearance receptors by EGF in mesangial cells from NOD mice.
S. Placier, X. Bretot, N. Ardaillou, J.-C. Dussaule, and R. Ardaillou (2001)
Am J Physiol Renal Physiol 281, F244-F254
   Abstract »    Full Text »    PDF »
Critical role for the docking-protein FRS2{alpha} in FGF receptor-mediated signal transduction pathways.
Y. R. Hadari, N. Gotoh, H. Kouhara, I. Lax, and J. Schlessinger (2001)
PNAS 98, 8578-8583
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Restricted Accumulation of Phosphatidylinositol 3-Kinase Products in a Plasmalemmal Subdomain during Fc{gamma} Receptor-Mediated Phagocytosis.
J. G. Marshall, J. W. Booth, V. Stambolic, T. Mak, T. Balla, A. D. Schreiber, T. Meyer, and S. Grinstein (2001)
J. Cell Biol. 153, 1369-1380
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PTEN Expression Causes Feedback Upregulation of Insulin Receptor Substrate 2.
L. Simpson, J. Li, D. Liaw, I. Hennessy, J. Oliner, F. Christians, and R. Parsons (2001)
Mol. Cell. Biol. 21, 3947-3958
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Identification of Epidermal Growth Factor Receptor- Grb2-associated Binder-1-SHP-2 Complex Formation and Its Functional Loss during Neoplastic Cell Progression.
H. Kameda, J. I. Risinger, B.-B. Han, S. J. Baek, J. C. Barrett, W. C. Glasgow, and T. E. Eling (2001)
Cell Growth Differ. 12, 307-318
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Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins.
S. H. Ong, Y. R. Hadari, N. Gotoh, G. R. Guy, J. Schlessinger, and I. Lax (2001)
PNAS 98, 6074-6079
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Scaffolding Protein Gab2 Mediates Differentiation Signaling Downstream of Fms Receptor Tyrosine Kinase.
Y. Liu, B. Jenkins, J. L. Shin, and L. R. Rohrschneider (2001)
Mol. Cell. Biol. 21, 3047-3056
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The Gab1 Docking Protein Links the B Cell Antigen Receptor to the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway and to the SHP2 Tyrosine Phosphatase.
R. J. Ingham, L. Santos, M. Dang-Lawson, M. Holgado-Madruga, P. Dudek, C. R. Maroun, A. J. Wong, L. Matsuuchi, and M. R. Gold (2001)
J. Biol. Chem. 276, 12257-12265
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A Critical Role for Phosphoinositide 3-Kinase Upstream of Gab1 and SHP2 in the Activation of Ras and Mitogen-activated Protein Kinases by Epidermal Growth Factor.
A. Yart, M. Laffargue, P. Mayeux, S. Chretien, C. Peres, N. Tonks, S. Roche, B. Payrastre, H. Chap, and P. Raynal (2001)
J. Biol. Chem. 276, 8856-8864
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The Epidermal Growth Factor Receptor Engages Receptor Interacting Protein and Nuclear Factor-{kappa}B (NF-{kappa}B)-inducing Kinase to Activate NF-{kappa}B: IDENTIFICATION OF A NOVEL RECEPTOR-TYROSINE KINASE SIGNALOSOME.
A. A. Habib, S. Chatterjee, S.-K. Park, R. R. Ratan, S. Lefebvre, and T. Vartanian (2001)
J. Biol. Chem. 276, 8865-8874
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Epidermal Growth Factor Receptor-dependent Control of Keratinocyte Survival and Bcl-xL Expression through a MEK-dependent Pathway.
M. Jost, T. M. Huggett, C. Kari, L. H. Boise, and U. Rodeck (2001)
J. Biol. Chem. 276, 6320-6326
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The Tyrosine Phosphatase SHP-2 Is Required for Sustained Activation of Extracellular Signal-Regulated Kinase and Epithelial Morphogenesis Downstream from the Met Receptor Tyrosine Kinase.
C. R. Maroun, M. A. Naujokas, M. Holgado-Madruga, A. J. Wong, and M. Park (2000)
Mol. Cell. Biol. 20, 8513-8525
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Cutting Edge: Gab2 Mediates an Inhibitory Phosphatidylinositol 3'-Kinase Pathway in T Cell Antigen Receptor Signaling.
J. C. Pratt, V. E. Igras, H. Maeda, S. Baksh, E. W. Gelfand, S. J. Burakoff, B. G. Neel, and H. Gu (2000)
J. Immunol. 165, 4158-4163
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Identification of an Atypical Grb2 Carboxyl-terminal SH3 Domain Binding Site in Gab Docking Proteins Reveals Grb2-dependent and -independent Recruitment of Gab1 to Receptor Tyrosine Kinases.
L. S. Lock, I. Royal, M. A. Naujokas, and M. Park (2000)
J. Biol. Chem. 275, 31536-31545
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New Role for Shc in Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway.
H. Gu, H. Maeda, J. J. Moon, J. D. Lord, M. Yoakim, B. H. Nelson, and B. G. Neel (2000)
Mol. Cell. Biol. 20, 7109-7120
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